Abnormalities of kidney and urinary tract development are the most common cause of chronic renal failure in children. While monogenetic renal dysgenesis syndromes continue to be unraveled, a sizable proportion of cases are sporadic and considered polygenic or a result of gene-environment interactions. During the previous funding period, we developed and characterized a unique mouse model of renal dysgenesis that is produced by defined gene-environment interactions. This animal model demonstrated that the bradykinin B2 receptor (B2R) is required for normal renal development under conditions of fetal stress. In response to gestational salt loading, B2R-null fetuses acquire a dysplastic renal phenotype characterized by excessive apoptosis, stromal expansion, and suppressed differentiated gene expression. Two independent lines of evidence support a central role for aberrant p53 activation in mediating the renal dysgenesis. First, the dysplastic kidneys overexpress a pro-apoptotic form of p53, P-Ser46-p53. Second, genetic crosses resulting in germline p53 haploinsufficiency rescue kidney development in salt-stressed B2R-null mutants. The long-term objective of this proposal is to elucidate the pathways leading to aberrant p53 activation and disruption of terminal epithelial differentiation in the developing kidney. Specific Aim 1 will test the hypothesis that induction of p53 in B2R-null embryos is kidney-restricted and is accompanied by activation/expression of upstream p53 stress-induced kinases. Specific Aim 2 will determine the direct role of P-Ser46-p53 in the pathogenesis of the renal dysgenesis using two complementary genetic approaches. The first involves p53 gene dosage reduction in the germline of B2R-null mice; the second, generation of B2R null mice harboring a mutant Ser46-to-Ala p53 allele. We postulate that, in both cases, the B2R-null progeny will be protected from the renal dysgenesis. Specific Aim 3 will test the hypothesis that P-Ser46-p53 suppresses differentiated gene expression through recruitment of histone deacetylases (HDAC) to the promoter regions of terminal differentiation genes. In addition, we will explore the potential therapeutic benefit of HDAC inhibitors in the restoration of terminal differentiation and halting progression of the renal dysgenesis. We anticipate that new pathogenetic paradigms and therapeutic strategies will emerge from our studies that can hopefully be applied for the treatment of renal dysgenesis. [unreadable] [unreadable]